Colucci R, Fornai M, Antonioli L, Ghisu N, Tuccori M, Blandizzi C, Del Tacca M
Interdepartmental Centre for Research in Clinical Pharmacology and Experimental Therapeutics, University of Pisa, Pisa, Italy.
Dig Liver Dis. 2009 Jun;41(6):395-405. doi: 10.1016/j.dld.2008.10.004. Epub 2009 Feb 28.
The efficacy of proton pump inhibitors in patients at high risk of gastrointestinal injury receiving non-steroidal anti-inflammatory drugs is currently debated.
To evaluate the effects of esomeprazole on the impairment of gastric ulcer healing associated with non-steroidal anti-inflammatory drug treatment.
Gastric ulcers were induced in rats by acetic acid. Four days later, animals were treated daily with equivalent acid-inhibiting doses of esomeprazole or famotidine, alone or in combination with indomethacin. At day 3 or 7 of treatment, ulcerated tissues were processed to assess: ulcer area; malondialdehyde; prostaglandin E(2); nuclear factor-kB; proliferating cell nuclear antigen and caspase-3 (Western blot).
In indomethacin-treated animals, esomeprazole was more effective than famotidine or the antioxidant melatonin in promoting ulcer healing. Malondialdehyde levels were increased by indomethacin, and this effect was counteracted by esomeprazole, but not famotidine. Esomeprazole and famotidine, given alone or in combination with indomethacin, increased proliferating cell nuclear antigen expression. Increased levels of prostaglandin E(2) were detected in ulcerated tissues. Ulcer prostaglandin E(2) production was reduced by indomethacin, alone or in combination with esomeprazole or famotidine, while it was enhanced when esomeprazole or famotidine were tested alone. The activation of caspase-3 was induced by indomethacin, and this effect was prevented by esomeprazole, but not famotidine. In the presence of indomethacin, esomeprazole, but not famotidine, enhanced nuclear factor-kB activation in gastric ulcers.
Esomeprazole counteracts the detrimental action of indomethacin on ulcer repair through both acid-dependent and acid-independent effects. The acid-independent actions are related to decrease in tissue oxidation and apoptosis and to enhancement of nuclear factor-kB activation.
质子泵抑制剂在接受非甾体抗炎药治疗且有胃肠道损伤高风险患者中的疗效目前存在争议。
评估埃索美拉唑对与非甾体抗炎药治疗相关的胃溃疡愈合受损的影响。
通过乙酸在大鼠中诱导胃溃疡。四天后，动物每天接受等效抑酸剂量的埃索美拉唑或法莫替丁治疗，单独使用或与吲哚美辛联合使用。在治疗的第3天或第7天，对溃疡组织进行处理以评估：溃疡面积；丙二醛；前列腺素E(2)；核因子-κB；增殖细胞核抗原和半胱天冬酶-3（蛋白质印迹法）。
在吲哚美辛治疗的动物中，埃索美拉唑在促进溃疡愈合方面比法莫替丁或抗氧化剂褪黑素更有效。吲哚美辛可增加丙二醛水平，而埃索美拉唑可抵消这种作用，但法莫替丁不能。单独使用或与吲哚美辛联合使用时，埃索美拉唑和法莫替丁均可增加增殖细胞核抗原的表达。在溃疡组织中检测到前列腺素E(2)水平升高。单独使用或与埃索美拉唑或法莫替丁联合使用时，吲哚美辛可降低溃疡前列腺素E(2)的产生，而单独测试埃索美拉唑或法莫替丁时则会增强其产生。吲哚美辛可诱导半胱天冬酶-3的激活，而埃索美拉唑可预防这种作用，但法莫替丁不能。在存在吲哚美辛的情况下，埃索美拉唑而非法莫替丁可增强胃溃疡中核因子-κB 的激活。
埃索美拉唑通过酸依赖性和酸非依赖性作用抵消吲哚美辛对溃疡修复的有害作用。酸非依赖性作用与组织氧化和细胞凋亡的减少以及核因子-κB 激活的增强有关。
